Monotherapy Of Farnesyl Transferase Inhibitors In Breast Cancer And Other Diseases

Table 1 summarizes the results of a phase I-II trial of tipifarnib monotherapy in patients with ER-positive metastatic breast cancer who have failed second-line endocrine therapy, or with ER-negative disease (37). Seventy-six patients received either 400 mg (N = 6) or 300 mg (N = 35) twice daily on a continuous schedule, or 300 mg BID using a 3-week on, 1-week off intermittent schedule (N = 35). The clinical benefit rate (partial response or stable for at least 24 weeks) was comparable in the continuous (25%) and intermittent schedules (23%). There was no statistical association between response to tipifarnib and tumor characteristics, such as the status of ER, HER2, and mutation in three ras genes. Sites of response occurred in liver, lung, pleura, lymph nodes, breast, and skin nodules. There was significantly less toxicity associated with the intermittent compared with the continuous schedule, including neutropenia, anemia, thrombocytopenia, and neurotoxicity. Although there was high interpersonal variability in pharmacokinetics of tipifarnib, no significant differences were observed between the two dosing regimens. Daily area under the curve (AUC) plasma concentration was found to be a better predictor for severe neutropenia than the administrated daily dose.

Hematologic improvement or remission has been reported in patients with acute leukemia or myelodysplastic syndrome (66-69). However, numerous phase II studies in patients with a variety of solid tumors other than breast cancer have not demonstrated any activity for FTIs when used as monotherapy (32). A phase

TABLE 1 Phase II Trial of Tipifarnib for Metastatic Breast Cancer

Continuous dosing

Intermittent dosing

No.

41

35

Dose

400 mg BID (N = 6) or 300 mg

300 mg BID

BID (N = 35)

Efficacy

Objective response

10%

14%

Stable disease >24 weeks

15%

9%

Clinical benefit rate

25% (95% CI, 12%, 40%)

23% (95% CI, 10%, 40%)

Median duration of benefit

11.9 mo (95% CI, 4.5, 14.0 mo)

8.7 mo (95% CI, 5.6, 13.3 mo)

Median time to progression

3.2 mo (95% CI, 2.8, 4.5 mo)

2.9 mo (95% CI, 2.0, 4.0 mo)

Median overall survival

15.1 mo (95% CI, 10.3, 21.1 mo)

10.4 mo (95% CI, 7.9, 16.6 mo)

Toxicity (grade 3-4)

43%a

14%

Neutropenia

9%a

0%

Anemia

26%a

3%

Thrombocytopenia

12%a

0%

aIncludes 300 mg BID dose only. Source: From Ref. 37.

aIncludes 300 mg BID dose only. Source: From Ref. 37.

III trial compared tipifarnib (300 mg twice a day given for 21 consecutive days every 28 days) with a placebo in 368 patients with metastatic colorectal carcinoma who had progressive disease after two prior chemotherapy regimens. This disease and setting were chosen because of the high rate of ras mutations in this disease (~50%), and the lack of a standard third-line treatment regimen at the time that the trial was performed. There was no significant difference in median progression-free survival or overall survival (5.7 months vs. 6.1 months, P = 0.396) (70).

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